Antibiotic resistant strains of bacteria as well as emerging bacterial pathogens pose a growing threat to world health, and the development of antibiotics necessary to counter these threats has dramatically slowed over the previous decades, leaving the population more vulnerable to these risks (Katz et al., 2006, Nat. Biotech. 24: 1529-1531; Payne et al., 2007, Nat. Rev. Drug Discovery 6: 29-40). Most newly developed antibiotics merely target one of the proven vulnerable pathways previously exploited by prior generations of antibiotics. While these drugs are effective, resistance to them is rising at an alarming rate, suggesting the need for antibiotics that target additional bacterial molecules or cellular processes.
Single-stranded DNA-binding proteins (SSBs) in bacteria form essential intermolecular complexes with at least a dozen other DNA replication, DNA recombination, and DNA repair proteins (Molineux and Gefter, 1975, J. Mol. Biol. 98: 811-825; Butland et al., 2005, Nature 433: 531-537). In addition, SSB proteins play important organizational roles through their interactions with many different genome maintenance proteins. Several, if not all, of these interactions are known to be mediated by the carboxy-terminal-most 8-10 residues from SSB, which form a peptide sequence that is highly conserved among bacterial SSBs but is not found in eukaryotic SSBs (Sandigursky et al., 1996, Radiation Res. 145: 619-623; Curth et al., 1996, Nucleic Acids Res. 24: 2706-2711; Genschel et al., 2000, Biol. Chem. 381: 183-192). Previous studies have shown that mutations within, or deletions of, this interaction sequence from SSB, have drastic effects on bacterial viability, indicating that formation of proper protein interactions with this site is critical for bacterial growth.
SSBs are a conserved protein family found throughout all forms of life, playing a variety of essential roles in nearly all aspects of DNA metabolism. SSBs bind and protect sensitive single-stranded DNA (ssDNA) intermediates that occur during DNA replication, recombination, and repair. SSBs recruit genome maintenance proteins to ssDNA, and play instrumental regulatory roles in ssDNA degradation, replication initiation, initiation of homologous recombination, relaxation of supercoiled DNA, and numerous other genome maintenance processes. Deletions of SSBs have been shown to be lethal and since all known SSBs play similar roles in cells, finding compounds that inhibit bacterial SSBs could have similar effects on eukaryotic cells.